Biochemical alterations of dopamine receptor responses following chronic L-dopa therapy

Abstract

The effects of chronic l-dopa treatment on rat striatal adenylate cyclase and dopaminereceptor binding activities were studied using an oral dose of Sinemet (250 mg l-dopa/25 mg carbidopa). The calculated average daily oral intake of l-dopa was 150 mg/rat. A 4-fold increase in the ec(50) for dopamine on adenylate cyclase activity in homogenstes of the caudate nucleus was observed in the oral drug-treated group with no change in the maximal level of enzyme activity. Binding studies using [(3)H]spiroperidol, a dopamine-receptor antagonist, revealed a decrease in the dissociation constant from 0.26 nM in the control group to 0.069 nM in the oral drug-treated group. In addition, the B(max) for [(3)H]spiroperidol specific binding in the animals receiving oral l-dopa increased by 300 fmoles/mg over that observed in the control group. Dopamine-sensitive adenylate cyclase and binding activities in animals receiving a lower dose of l-dopa alone, given intraperitoneally (50 mg/kg) twice daily, were determined to be similar to control values. Analysis of the cerebrospinal fluid biogenic amine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), by gas chromatography/mass spectrometry revealed a 13-fold increase in HVA following oral l-dopa and a 44 per cent increase in MHPG levels. These data, which demonstrate an increased number of dopamine binding sites following long-term l-dopa therapy, are consistent with demonstrations of behavioral hypersensitivity in animals undergoing this particular drug treatment. The results also suggest that the subsensitivity of the adenylate cyclase system may reflect a side effect of this drug, due to prolonged administration.